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PRCCs with high ABCC2 expression represent an aggressive subset frequently associated with metastasis. The tumor microenvironment (TME) profile of these tumors remains poorly defined. This study aims to characterize the TME of PRCC in relation to its ABCC2 status. A discovery cohort of 157 ABCC2\u2010high PRCCs, 156 ABCC2\u2010low PRCCs, and 72 normal kidneys was evaluated. Using RNA sequencing data, immune cell composition, immune checkpoint markers, and immune signature scores were assessed. Validation was performed in an independent cohort (31 ABCC2\u2010high, 36 ABCC2\u2010low, and 15 normal kidneys) using RNA\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization (RNA\u2010ISH) and immunohistochemistry (IHC). ABCC2\u2010high PRCCs demonstrated increased infiltration of cytotoxic T cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), M2 macrophages (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.021), and regulatory T cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) compared to ABCC2\u2010low tumors. ABCC2\u2010high PRCCs also had higher expression of immune checkpoint biomarkers including programmed cell death ligand 1 (PD\u2010L1) (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). The validation cohort showed this similar TME profile. Additionally, ABCC2\u2010high PRCCs had higher PD\u2010L1 IHC positivity (combined positive score\u2009\u2265\u20091,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.035; tumor proportion score\u2009\u2265\u20091%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.006) and immune predictive signature score (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.029). NRF2\u2013Antioxidant Response Element signaling pathway was enriched in ABCC2\u2010high PRCCs as evidenced by overrepresentation in pathway analysis, higher gene signature score (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), and elevated transcript signals (\n                    <jats:italic>NFE2L2<\/jats:italic>\n                    ,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001;\n                    <jats:italic>NQO1<\/jats:italic>\n                    ,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), compared to ABCC2\u2010low PRCCs. In conclusion, ABCC2\u2010high PRCCs are immune\u2010infiltrated tumors with a suppressive phenotype potentially responsive to immune checkpoint inhibitors. ABCC2 IHC may serve as a predictive biomarker to help identify patients likely to benefit from such therapy. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70001","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:50:24Z","timestamp":1763567424000},"page":"188-199","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Papillary renal cell carcinoma with high\u2010\n                    <scp>ABCC2<\/scp>\n                    shows an immune\u2010evasive profile associated with favorable response to immunotherapy"],"prefix":"10.1002","volume":"268","author":[{"given":"Vincent 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